Use of certain substituted caprolactams in treating tumors

ABSTRACT

The present invention relates to certain substituted caprolactam compounds, pharmaceutical compositions containing said compounds, the use of said compounds in treating tumors and to a process for making said compounds.

[0001] This is a continuation-in-part of U.S. application Ser. No.09/441,739, filed Nov. 17, 1999, which application claims the benefit ofU.S. Provisional application Ser. No. 60/172,254, filed Nov. 17, 1998,which was converted from U.S. application Ser. No. 09/193,354, and whichis incorporated herein by reference.

[0002] The present invention relates to the area of chemotherapeuticagents and, more particularly, relates to certain substitutedcaprolactams, pharmaceutical compositions comprising said caprolactams,a method of treating tumors, the use of said caprolactams in thechemotherapy of tumors, and a process for preparing said compounds.

[0003] Cancer is a serious health problem throughout the world. As aresult, an extensive number of research endeavors has been undertaken inan effort to develop therapies appropriate to the treatment andalleviation of cancer in humans.

[0004] In the chemotherapeutic area, research has been conducted todevelop anti-tumor agents effective against various types of cancer.Oftentimes, anti-tumor agents which have been developed and foundeffective against cancer cells are, unfortunately, also toxic to normalcells. This toxicity manifests itself in weight loss, nausea, vomiting,hair loss, fatigue, itching, hallucinations, loss of appetite, etc.,upon administration of the anti-tumor agent to a patient in need ofcancer chemotherapy.

[0005] Furthermore, conventionally used chemotherapeutic agents do nothave the effectiveness desired or are not as broadly effective againstdifferent types of cancers as desired. As a result, a great need existsfor chemotherapeutic agents which are not only more effective againstall types of cancer, but which have a higher degree of selectivity forkilling cancer cells with no or minimal effect on normal healthy cells.In addition, highly effective and selective anti-tumor agents, inparticular, against cancers of the colon, bladder, prostate, stomach,pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulvaand small intestine are desired. Moreover, anti-tumor activity againstcolon, breast, lung and prostate cancers as well as melanomas areparticularly desired because of the lack of any particular effectivetherapy at the present time.

[0006] The present invention provides new anti-tumor agents which areeffective against a variety of cancer cells. More particularly, thepresent invention relates to certain substituted caprolactams whichexhibit a high degree of selectivity in killing cancer cells. Theessence of the instant invention is the finding that certain substitutedcaprolactams are useful in treating tumors.

[0007] The invention relates to caprolactams of formula I:

[0008] where

[0009] R₁ is (C₁₋₆)alkyl or (C₃₋₆)cycloalkyl;

[0010] R₂ is hydrogen or (C₁₋₆)alkyl;

[0011] X is (C₁₋₁₂) alkylene; (C₂₋₁₂) alkenylene; or (C₂₋₁₂) alkynylene;

[0012] m is 0 or 1; and

[0013] R₃ is (C₃₋₈)cycloalkyl; or an aromatic ring system selected fromII, III, IV and V:

[0014] where

[0015] R₄ is hydrogen, chloro, or methoxy;

[0016] R₅ is hydrogen, chloro, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z isoxygen, sulfur, N—H, or N—CH₃;

[0017] or a pharmaceutically acceptable acid addition salt thereof,where possible.

[0018] Preferred compounds of formula I are those where

[0019] R₁ is (C₁₋₆) alkyl;

[0020] R₂ is hydrogen or (C₁₋₄) alkyl;

[0021] X is (C₁₋₆) alkylene or (C₂₋₆) alkenylene;

[0022] m is 0 or 1; and

[0023] R₃ is (C₃₋₈)cycloalkyl; or an aromatic ring system selected fromII, III, IV and V where

[0024] R₄ is hydrogen, chloro, or methoxy;

[0025] R₅ is hydrogen, chloro, (C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z isoxygen, sulfur, N—H, or N—CH₃;

[0026] or a pharmaceutically acceptable acid addition salt thereof,where possible.

[0027] More preferred compounds are those of formula I where

[0028] R₁ is i-propyl or t-butyl;

[0029] R₂ is hydrogen or methyl;

[0030] m is 0 or 1;

[0031] X is (C₁₋₆) alkylene; and

[0032] R₃ is (C₅₋₇)cycloalkyl; or an aromatic ring system selected fromIIa and V:

[0033] where

[0034] R₄′ is in the meta position and is hydrogen or chloro; and

[0035] R₅′ is in the para position and is hydrogen, chloro, (C₁₋₁₈)alkylor (C₁₋₁₈)alkoxy;

[0036] or a pharmaceutically acceptable acid addition salt thereof,where possible.

[0037] Even more preferred compounds are those of formula I where

[0038] R₁ is i-propyl or t-butyl;

[0039] R₂ is hydrogen or methyl;

[0040] m is 0or 1;

[0041] X is methylene or ethylene; and

[0042] R₃ is (C₅₋₇)cycloalkyl, phenyl, 3,4-dichlorophenyl,4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenyl or 3-pyridyl;

[0043] with the proviso that when m is 0, R₃ is (C₅₋₇)cycloalkyl,4-n-decylphenyl or 4-n-decyloxyphenyl;

[0044] or a pharmaceutically acceptable acid addition salt thereof,where possible.

[0045] In another embodiment, the instant invention providespharmaceutical compositions, especially for the treatment of tumors inwarm-blooded animals, comprising a pharmaceutically acceptable carrieror diluent and an antitumorally effective dose of a compound of formulaI above, preferably3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamideor3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl]non-6-enamide,or a pharmaceutically acceptable acid addition salt thereof, wherepossible.

[0046] In still another embodiment, the instant invention provides amethod for treating tumors comprising administering to a mammal in needof such treatment a therapeutically effective amount of a compound offormula I above, or a pharmaceutically acceptable acid addition saltthereof, where possible.

[0047] In another embodiment, the instant invention relates to the useof a compound of formula I or of a pharmaceutically acceptable salt ofsuch a compound for the preparation of a pharmaceutical composition foruse in the chemotherapy of tumors.

[0048] Furthermore, the instant invention relates to the use of acompound of formula I or of a pharmaceutically acceptable salt of such acompound for the chemotherapy of tumors.

[0049] In the above definitions: 1) the alkyl groups containing 1 to 6carbon atoms are either straight or branched chain, of which examples ofthe latter include isopropyl, isobutyl, t-butyl, isopentyl, neopentyl,isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and1,1,2,2-tetramethylethyl; and 2) the alkyl and alkoxy groups containing1 to 18 carbon atoms are either straight or branched chain.

[0050] The term “(C₁₋₁₂) alkylene” as used herein refers to a straightor branched chain divalent group consisting solely of carbon andhydrogen and having from 1 to 12 carbon atoms. Examples of “alkylene”groups include methylene, ethylene, propylene, butylene, pentylene,3-methypentylene, etc.

[0051] The term “(C₂₋₁₂) alkenylene” as used herein refers to a straightor branched chain divalent group consisting solely of carbon andhydrogen, containing at least one carbon-carbon double bond, and havingfrom 2 to 12 carbon atoms. Examples of “alkenylene” groups includeethenylene, propenylene, butenylene, pentenylene, 3-methylpentenylene,etc.

[0052] The term “(C₂₋₁₂) alkynylene” as used herein refers to a straightor branched chain divalent group consisting solely of carbon andhydrogen, containing at least one carbon-carbon triple bond, and havingfrom 2 to 12 carbon atoms. Examples of “alkynylene” groups includeacetylene, propynylene, butynylene, pentynylene, 3-methylpentynylene,etc.

[0053] The acid addition salts of the compounds of formula I may bethose of pharmaceutically acceptable organic or inorganic acids.Although the preferred acid addition salts are those of hydrochloric andmethanesulfonic acid, salts of sulfuric, phosphoric, citric, fumaric,maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and aceticacid may also be utilized.

[0054] The caprolactams of formula I may be prepared as depicted below:

[0055] where each R₁, R₂, X, m and R₃ is as defined above.

[0056] As to the individual steps, Step A involves the acylation of anaminocaprolactam of formula VI with a lactone compound of formula VII toobtain a diamide compound of formula VIII. The acylation is conducted ina polar, organic solvent, preferably a protic polar solvent such asisopropanol, at a temperature slightly below or at the refluxtemperature of the solvent employed for a period of between 4 and 48hours.

[0057] Alternatively, the acylation of an aminocaprolactam of formulaVI, or an acid addition salt thereof, with the lactone compound offormula VII in Step A may be carried out with in the presence of: 1) aweak base, preferably a carboxylate salt such as sodium2-ethylhexanoate, and 2) a polar, organic solvent, preferably an ethersuch as tetrahydrofuran, at a temperature of between 0° C. and 50° C.,preferably at 25° C., for a period of between 1 hour and 7 days,preferably for 20 hours.

[0058] Step B concerns the hydrolysis of the 1,3-dioxane group common toa diamide compound of formula VIII, to obtain a substituted caprolactamcompound of formula I. The hydrolysis is typically carried out bydissolving the diamide in a mixture of solvents consisting of 1) aprotic acid, preferably an organic acid such as trifluoroacetic acid, 2)a protic solvent, preferably water, and 3) an inert organic solvent,preferably a cyclic ether such as tetrahydrofuran, at a temperature ofbetween 0° C. and 25° C. for a period of between 5 minutes and 2 hours.

[0059] Alternatively, the diamide compounds of formula VIII may beprepared according to the following 3-step reaction scheme:

[0060] where X, m and R₃ and each R₁ and R₂ are as defined above, and R₆is an alcohol protective group. Preferably, R₆ is a silyl group such astert-butyldimethylsilyl.

[0061] As to the individual steps, Step 1 involves the acylation of anaminocaprolactam of formula IX with a lactone compound of formula VII toobtain a diamide compound of formula X. The acylation is conducted inthe presence of a base, preferably an alkylamine base such asdiisopropylethylamine, and a polar, organic solvent, preferably a proticpolar solvent such as isopropanol, at a temperature slightly below or atthe reflux temperature of the solvent employed for a period of between 4and 48 hours.

[0062] Step 2 concerns the hydrolysis of the group R₆ common to adiamide compound of formula X to obtain a hydroxycaprolactam compound offormula XI. The hydrolysis is typically carried out in the presence offluoride, preferably a fluoride salt such as tetrabutyl-ammoniumfluoride, and an inert organic solvent, preferably a cyclic ether suchas tetrahydrofuran, at a temperature of between 0° C. and 25° C. for aperiod of between 5 minutes and 2 hours.

[0063] Step 3 concerns the acylation of a hydroxycaprolactam compound offormula XI by reacting it with an acid chloride of formula R₃(X)_(m)COCIwhere R₃, X and m are as defined above, to obtain a diamide compound offormula VIII. The acylation is conducted in the presence of a base,preferably an alkylamine base such as triethylamine, and an inertorganic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C and 25° C. for aperiod of between 1 and 24 hours.

[0064] Alternatively, the acylation of a hydroxycaprolactam compound offormula XI in Step 3 may be carried out with a carboxylic acid offormula R₃(X)_(m)CO₂H where R₃, X and m are as defined above, in thepresence of a carboxylic acid coupling reagent, preferably a diimidesuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, anda suitable activating agent common to diimide coupling reactions,preferably a substituted pyridine such a 4-dimethylaminopyridine, and aninert organic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C. and 25° C. for aperiod of between 1 and 24 hours.

[0065] The aminocaprolactam compounds of formula VI may be prepared asdepicted below:

[0066] where each R₆, R₂, X, m and R₃ is as defined above, and each R₇is a carbonyl-containing group. Preferably, R₇ is alkoxycarbonyl such ast-butyloxycarbonyl.

[0067] As to the individual steps, Step 1a involves the cyclization ofhydroxylysine (or any salt or hydrate preparation thereof) XII to obtainhydroxycyclolysine XIII. The cyclization is typically carried out in thepresence of a coupling reagent, preferably a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and asuitable activating agent common to diimide coupling reactions,preferably an N-hydroxy compound such as 1-hydroxybenztriazole hydrate,and a base, preferably an alkylamine base such as triethylamine, and apolar organic solvent, preferably an amide such asN,N-dimethylformamide, at a temperature of between 0° C. and 40° C. fora period of between 12 and 72 hours.

[0068] Step 2a involves the N-acylation of hydroxycyclolysine XIII toobtain an N-acylhydroxycyclolysine compound of formula XIV. Theacylating agent is typically an acid chloride or an anhydride. When R₇is t-butyloxycarbonyl, the acylating agent is di-tert-butyldicarbonate.The reaction is carried out in the presence of a base, preferably analkylamine base such as triethylamine, and a polar organic solvent,preferably an amide such as N,N-dimethylformamide, at a temperature ofbetween 0° C. and 40° C. for a period of between 1 and 24 hours.

[0069] Step 3a involves the O-silylation of an N-acylhydroxycyclolysinecompound of formula XIV to obtain a silyl ether compound of formula XV.The silylating agent is typically a silyl chloride ortrifluoromethanesulfonate. When R₆ is tert-butyldimethylsilyl, thesilylating agent is tert-butyldimethylsilylchloride. The reaction iscarried out in the presence of a base, preferably a mild base such asimidazole, and a polar organic solvent, preferably an amide such asN,N-dimethylformamide, at a temperature of between 0° C. and 40° C. fora period of between 1 and 24 hours.

[0070] Step 4a involves the N-alkylation of a silyl ether compound offormula XV with an alkyl (defined as R₂ above) halide or sulfonate toobtain an N-alkyl caprolactam compound of formula XVI. The alkylation isconducted in the presence of a strong base, preferably an alkali metalamide such as sodium bis(trimethylsilyl)amide, and an inert organicsolvent, preferably a cyclic ether such as tetrahydrofuran, at atemperature of between −100° C. and 25° C. for a period of between 5minutes and 2 hours.

[0071] Step 5a concerns the hydrolysis of the group R₆ common to anN-alkyl caprolactam compound of formula XVI, to obtain ahydroxycaprolactam compound of formula XVII. The hydrolysis is typicallycarried out in the presence of fluoride, preferably a fluoride salt suchas tetrabutylammonium fluoride, and an inert organic solvent, preferablya cyclic ether such as tetrahydrofuran, at a temperature of between 0°C. and 25° C. for a period of between 5 minutes and 2 hours.

[0072] Step 6a concerns the acylation of a hydroxycaprolactam compoundof formula XVII to obtain an ester compound of formula XVIII by reactingit with an acid chloride of formula R₃(X)_(m)COCI where R₃, X and m areas defined above, in the presence of a base, preferably an alkylaminebase such as triethylamine, and an inert organic solvent, preferably achlorinated alkane such as dichloromethane, at a temperature of between−78° C. and 25° C. for a period of between 1 and 24 hours.

[0073] Alternatively, the acylation of a hydroxycaprolactam compound offormula XVII in Step 6a may be carried out with a carboxylic acid offormula R₃(X)_(m)CO₂H where R₃, X and m are as defined above, in thepresence of a carboxylic acid coupling reagent, preferably a diimidesuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, anda suitable activating agent common to diimide coupling reactions,preferably a substituted pyridine such a 4-dimethylaminopyridine, and aninert organic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C. and 25° C. for aperiod of between 1 and 24 hours.

[0074] Step 7a concerns the hydrolysis of the group R₇ on an estercompound of formula XVIII to obtain an aminocaprolactam compound offormula VI. The hydrolysis is typically carried out in the presence of aprotic acid, preferably an organic acid such as trifluoroacetic acid,hydrogen or a silyl halide, preferably a silyl iodide such astrimethylsilyl iodide, and an inert organic solvent, preferably achlorinated alkane such as dichloromethane, at a temperature of between−100° C. and 25° C. for a period of between 1 minute and 2 hours.

[0075] The aminocaprolactam compounds of formula VIa may be prepared asdepicted below:

[0076] where each R₇, X, m, and R₃ is as defined above.

[0077] As to the individual steps, Step 1b concerns the acylation of ahydroxycaprolactam compound of formula XIV to obtain an ester compoundof formula XVIIIa by reacting it with an acid chloride of formulaR₃(X)_(m)COCI where R₃, X and m are as defined above, in the presence ofa base, preferably an alkylamine base such as triethylamine, and aninert organic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C. and 25° C. for aperiod of between 1 and 24 hours.

[0078] Alternatively, the acylation of a hydroxycaprolactam compound offormula XIV in Step 1b may be carried out with a carboxylic acid offormula R₃(X)_(m)CO₂H where R₃, X and m are as defined above, in thepresence of a carboxylic acid coupling reagent, preferably a diimidesuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, anda suitable activating agent common to diimide coupling reactions,preferably a substituted pyridine such a 4-dimethylaminopyridine, and aninert organic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −78° C. and 25° C. for aperiod of between 1 and 24 hours.

[0079] Step 2b concerns the hydrolysis of the group R₇ on an estercompound of formula XVIIIa to obtain an aminocaprolactam compound offormula VIa. The hydrolysis is typically carried out in the presence ofan protic acid, preferably an organic acid such as trifluoroacetic acid,hydrogen or a silyl halide, preferably a silyl iodide such astrimethylsilyl iodide, and an inert organic solvent, preferably achlorinated alkane such as dichloromethane, at a temperature of between−100° C. and 25° C. for a period of between 1 minute and 12 hours.

[0080] The aminocaprolactam compounds of formula IXa may be prepared asdepicted below:

[0081] where R₇ and each R₆ are as defined above. The reaction concernsthe hydrolysis of the group R₇ on an ester compound of formula XV toobtain an aminocaprolactam compound of formula IXa. The hydrolysis istypically carried out in the presence of a protic acid, preferably anorganic acid such as trifluoroacetic acid, hydrogen or a silyl halide,preferably a silyl iodide such as trimethylsilyl iodide, and an inertorganic solvent, preferably a chlorinated alkane such asdichloromethane, at a temperature of between −100° C. and 25° C. for aperiod of between 1 minute and 2 hours.

[0082] The lactone compounds of formula VII may be prepared as depictedbelow:

[0083] where R₁ is as defined above.

[0084] As to the individual steps, Step 1c involves the diketalizationof polyhydroxylated lactone of formula XIX with acetone to obtainbis(acetonide) XX. The diketalization is conducted in acetone as solventusing a catalyst such as iodine at a temperature of between 0° C. andthe reflux temperature for a period of between 2 and 48 hours.

[0085] Step 2c involves the methylation of bis(acetonide) XX with amethylating agent such as methyl iodide to obtain the methyl ether XXI.The methylation is conducted in the presence of water and a base,preferably a metal oxide such as silver oxide, and an inert organicsolvent, preferably a chlorinated alkane such as dichloromethane, at atemperature of between 0° C. and the reflux temperature for a period ofbetween 12 hours and 7 days.

[0086] Step 3c involves the hydrolysis of methyl ether XXI to obtain thedihydroxy compound of formula XXII. The hydrolysis is conducted in thepresence of water and a protic acid, preferably a carboxylic acid suchas acetic acid, at a temperature of between 5° C. and 35° C. for aperiod of between 1 and 24 hours.

[0087] Step 4c involves the oxidative cleavage of dihydroxy compoundXXII to obtain the aldehyde XXIII. The reaction is conducted in thepresence of an oxidant, preferably a periodate salt such as sodiumperiodate, in a protic solvent, preferably an alkanol such as methanol,at a temperature of between 0° C. and 25° C. for a period of between 10minutes and 4 hours.

[0088] Step 5c involves the olefination of aldehyde XXIII to obtain alactone compound of formula VII. The olefination is conducted in thepresence of an organometallic compound, preferably an organochromiumcompound such as the transient species generated fromchromium(II)chloride and a diiodoalkane (defined as R₁CHI₂where R₁ is asdefined above), in the presence of a solvent mixture consisting of 1) apolar organic solvent, preferably an amide such asN,N-dimethylformamide, and 2) an inert organic solvent, preferably acyclic ether such as tetrahydrofuran, at a temperature of between −80°C. and 25° C. for a period of between 5 minutes and 4 hours.

[0089] Although the product of each reaction described above may, ifdesired, be purified by conventional techniques such as chromatographyor recrystallization (if a solid), the crude product of one reaction isadvantageously employed in the following reaction without purification.

[0090] As is evident to those skilled in the art, the substitutedcaprolactam compounds of formula I contain asymmetric carbon atoms. Itshould be understood, therefore, that the individual stereoisomers arecontemplated as being included within the scope of this invention.

[0091] As indicated above, certain of the compounds of formula I formpharmaceutically acceptable acid addition salts. For example, the freebase of a compound of formula I can be reacted with hydrochloric acid toform the corresponding hydrochloride salt form, whereas reacting thefree base of the compound of formula I with methanesulfonic acid formsthe corresponding mesylate salt form. All pharmaceutically acceptableaddition salt forms of the compounds of formula I are intended to beembraced by the scope of this invention.

[0092] In a further embodiment, the present invention relates to aprocess for preparing a caprolactam compound of formula I whichcomprises, in a first step, acylating an amino caprolactam compound offormula VI

[0093] with a lactone compound of formula VII

[0094] in the presence of a polar, organic solvent to obtain a diamidecompound of formula VIII

[0095] where each of R₁, R₂, X, m and R₃ are as defined above and, in asecond step, hydrolyzing the diamide compound obtained in the first stepby dissolving it in a mixture of solvents to obtain the desiredcaprolactam compound of formula I. Preferably, the acylation in thefirst step is conducted in isopropanol at a temperature slightly belowor at the reflux temperature of the isopropanol, whereas the hydrolysisin the second step is conducted in a mixture consisting of a protic,organic acid, a protic solvent and an inert, organic solvent, morepreferably a mixture consisting of trifluoroacetic acid, water andtetrahydrofuran.

[0096] As indicated above, all of the compounds of formula I, and theircorresponding pharmaceutically acceptable acid addition salts, areanti-tumor agents and are, therefore, useful in inhibiting the growth ofvarious lymphomas, sarcomas, carcinomas, myelomas, and leukemia celllines. The anti-tumor activity of the compounds of formula I may bedemonstrated employing the Anchorage Dependent Growth Monolayer Assay(ADGMA) which measures the growth inhibitory effects of test compoundson proliferation of adherent cell monolayers. This assay was adaptedfrom the 60 cell line assay used by the National Cancer Institute (NCI)with the following modifications: 1) cell lines representative for theimportant tumor types, viz., MDA-MB-435 breast, A549 non-small celllung, HCT-116 colon and PC-3 prostate carcinomas were utilized; and 2) atetrazolium derivative, viz., MTS, was utilized to determine celldensity.

[0097] The ADGMA compares the number of viable cells following a 3-dayexposure to a test compound relative to a number of cells present at thetime the test compound was added.

[0098] Cell viability is measured using a tetrazolium derivative, viz,3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt (MTS) that is metabolically reduced in the presence of anelectron coupling agent (PMS; phenazine methosulfate) by viable cells toa water-soluble formazan derivative. The absorbance at 490 nm (A₄₉₀) ofthe formazan derivative is proportional to the number of viable cells.The IC₅₀ for a test compound is the concentration of compound requiredto reduce the final cell number to 50% of the final control cell number.If cell proliferation is inhibited, the assay further defines compoundsas cytostatic (cell number after 3-day compound incubation>cell numberat time of compound addition) or cytotoxic (cell number after 3-daycompound incubation<cell number at time of compound addition).

[0099] The MDA-MB-435 breast carcinoma line was obtained from theAmerican Type Culture Collection (ATCC) and used between passages 4-20following thawing. MDA-MB-435 breast carcinoma was maintained and platedin DME/F12 medium containing 10% fetal bovine serum, 15 mM HEPES(pH=7.4), 100 units/mL penicillin, and 100 μg/mL streptomycin.

[0100] The A549 non-small cell lung, HCT-116 colon, and PC-3 prostatecarcinoma lines were obtained from the American Type Culture Collection(ATCC) and used between passages 4-20 following thawing. A549, HCT-116and PC-3 cells were maintained in RPMI 1640 containing 5% FBS, 5 mg/mLinsulin, 5 mg/mL transferrin, 5 mg/mL selenous acid, 1 nM β-estradiol, 1nM testosterone, 100 units/mL penicillin and 100 μg/mL streptomycin.

[0101] Cell lines are trypsinized and counted using a Coulter counter todetermine plating densities. Cells are then plated in their respectivemaintenance media (100 μL/well) in 96 well plates at the followingdensities: MDA-MB-435, 3,000 cells/well; A549 and HCT-116, 700cells/well; are PC-3, 2500 cells/well. The number of cells plates asdetermined in preliminary experiments, results in cell densities of75-90% of confluency by 4 days after plating. Initial cell densities,assayed one day after plating, are roughly 0.15-0.20 absorbance unitsgreater than the media blank. Ninety-six well plates are seeded on day 0and the test compounds are added on day 1. A control plate is createdfor each cell line that receives media only in row A and cells in row B.One day following plating, test compounds are added (in a final volumeof 100 μL) to the test plates. Control plates receive 10 μL MTS mixture(prepared fresh on day of addition to cell plates at a ratio of 10 μL ofa 0.92 mg/mL solution of PMS to a 190 μL of a 2 mg/mL solution of MTS)and 100 μL media. A₄₉₀ of control plates is read 4h after MTS additionto determine initial cell density values for each cell line. Three daysafter addition of test compound, 10 μL/well of MTS mixture is added tothe test plates and A₄₉₀ is read 4h later. A₄₉₀ values for wellscontaining cells are corrected for media absorbance, then normalized toinitial density readings to determine percent net growth. IC₅₀ valuesare determined from graphs of percent net growth as a function ofcompound concentration. Percent net growth is calculated as (Cell+DrugA₄₉₀−Initial A₄₉₀/Cell+Drug Vehicle A₄₉₀−Initial A₄₉₀).

[0102] The following IC₅₀ values (average±S.D.) in μM were obtained:TABLE 1a Compound MDA-MB-435 Ex. 1 0.041 ± 0.026 Ex. 2 0.128 ± 0.047 Ex.3 0.032 ± 0.014 Ex. 4 0.012 ± 0.014 Ex. 5 0.465 ± 0.204 Ex. 6 0.065 ±0.001 Ex. 7 0.262 ± 0.07  Ex. 8 0.174 ± 0.007 Ex. 9 0.335 ± 0.141  Ex.10 0.006 ± 0.004  Ex. 11 0.019 ± 0.005  Ex. 12 0.027 ± 0.037  Ex. 130.300 ± 0.003  Ex. 14 1.238 ± 0.196 doxorubicin 0.399 ± 0.314 (a knownantineoplastic compound)

[0103] TABLE 1b Compound A549 Ex. 1 0.078 ± 0.038 Ex. 2 0.201 ± 0.100Ex. 4 0.020 ± 0.009 Ex. 5 1.045 ± 0.758 doxorubicin 0.504 ± 0.320

[0104] TABLE 1c Compound HCT-116 Ex. 1 0.041 ± 0.003 Ex. 2 0.120 ± 0.029Ex. 4 0.007 ± 0.003 Ex. 5 0.464 ± 0.142 doxorubicin 0.039 ± 0.006

[0105] TABLE 1d Compound PC-3 Ex. 1 0.039 ± 0.013 Ex. 2 0.145 ± 0.053Ex. 4 0.007 ± 0.004 Ex. 5 0.348 ± 0.026 doxorubicin 0.327 ± 0.123

[0106] The anti-tumor activity of the compounds of formula I may furtherbe demonstrated employing the athymic (T cell deficient) nude mousemodel which has been and remains the standard for drug discovery anddevelopment in preclinical oncology. Utilizing this model, one canmeasure the ability of test compounds to inhibit the growth of humantumor xenografts growing subcutaneously (s.c.) in athymic nude mice. Thehistologic tumor types employed were MDA-MB-435 breast, A549 non-smallcell lung, HCT-116 colon and PC-3 prostate carcinomas.

[0107] MDA-MB-435 breast carcinoma xenograft model: Briefly, 3 millioncells were implanted s.c. into the right flank of athymic (nu/nu) mice,and were allowed to grow until a mass of approximately 30 mm³ wasestablished. The test compounds are administered three times per weekintravenously (i.v.) for three weeks in 5% dextrose, 10%DMSO in water.The test compounds are administered in dose-response fashion in order toevaluate and document the full potential range of activity (efficacy andtoxicity) for a given compound. Positive controls are carried out withdoxorubicin administered 3 times per week i.v.

[0108] A549 non-small cell lung carcinoma xenograft model: Briefly, 10million cells were implanted s.c. into the right flank of athymic(nu/nu) mice, and were allowed to grow until a mass of approximately 120mm³ was established. The test compounds are administered three times perweek intravenously (i.v.) for three weeks in 5% dextrose, 10%DMSO inwater. The test compounds are administered in dose-response fashion inorder to evaluate and document the full potential range of activity(efficacy and toxicity) for a given compound. Positive controls arecarried out with mitomycin C administered 3 times per weekintraperitioneally (i.p.)

[0109] HCT-116 colon carcinoma xenograft model: Briefly, 3.5 millioncells were implanted s.c. into the right flank of athymic (nu/nu) mice,and were allowed to grow until a mass of approximately 45 mm³ wasestablished. The test compounds are administered three times per weekintravenously (i.v.) for three weeks in 5% dextrose, 10%DMSO in water.The test compounds are administered in dose-response fashion in order toevaluate and document the full potential range of activity (efficacy andtoxicity) for a given compound. Positive controls are carried out with5-fluorouracil administered 1 time per week i.v.

[0110] PC-3 prostate carcinoma xenograft model: Briefly, approximately20 mm³ fragments were implanted s.c. into the right flank of athymic(nu/nu) mice, and were allowed to grow until a mass of approximately 100mm³ was established. The test compounds are administered three times perweek intravenously (i.v.) for three weeks in 5% dextrose, 10%DMSO inwater. The test compounds are administered in dose-response fashion inorder to evaluate and document the full potential range of activity(efficacy and toxicity) for a given compound. Positive controls arecarried out with paclitaxel (dissolved in 12.5% cremophore/12.5%ethanol/0.9% saline solution) administered i.v. daily for the first fivedays of the study.

[0111] Toxicity was monitored by recording average group body weightstwice weekly, and by daily observation of general health. Efficacy wasmonitored by taking measurements of tumor length, width, and depthweekly using digital calipers coupled to automated data collectors. Meantumor volume (MTV) at initiation of therapy was subtracted from finalMTV in order to express the actual tumor growth during treatment (ΔMTV). Anti-tumor activity was expressed as %T/C (Δ MTV of treatedgroup÷Δ MTV of control group×100). Regressions were calculated using theformula: (T/T₀−1)×100%, where T is the tumor volume for the treatmentgroup at the end of the experiment, and T₀ is the tumor volume at thebeginning of the experiment. Statistical significance was evaluatedusing a one-tailed Student's t-test (p<0.05).

[0112] The following results were obtained for compounds of Ex.1- Ex.12tested against MDA-MB-435 tumor xenografts 3X/week for 3 weeks: TABLE 2aDose Δ MTV % T/C or % Compound (μmol/kg) (mm³) regression Dead/Total Ex.1 10 107  61* 0/8 Ex. 1 33 43 24* 0/8 Ex. 1 100  −11  29 regression* 0/8Ex. 2 10 94 67  0/8 Ex. 2 33 19 13* 0/8 Ex. 3 10 69 39* 0/8 Ex. 3 33 4928* 0/8 Ex. 4 10 93 53* 0/8 Ex. 4 33 21 12* 0/8 Ex. 4 100  −23  58regression* 0/8 Ex. 5 10 130  92  0/8 Ex. 5 33 62 44* 0/8 Ex. 6 10 6647* 0/8 Ex. 6 33 48 34* 0/8 Ex. 7 10 101  72  0/8 Ex. 7 33 61 43* 0/8Ex. 8 10 87 62  0/8 Ex. 8 33 94 67  0/8 Ex. 9 10 107  76  0/8 Ex. 9 3368 48* 0/8  Ex. 10 10 115  64* 0/8  Ex. 10 33  4  2* 0/8  Ex. 11 10 135 76  0/8  Ex. 11 33 76 43* 0/8  Ex. 12 10 78 52  0/8  Ex. 12 33 11  7*0/8 doxorubicin 2 mg/kg 74 42* 0/8

[0113] The following results were obtained for compounds of Ex.'s 1, 2,4, and 5 tested against A549 tumor xenografts 3X/week for 3 weeks: TABLE2b Dose Δ MTV % T/C or % Compound (μmol/kg) (mm³) regression Dead/TotalEx. 1 10 32 42  0/8 Ex. 1 33 29 38  0/8 Ex. 1 100  11 14* 1/8 Ex. 2 1044 58  0/8 Ex. 2 33 28 37* 0/8 Ex. 2 100   7  9* 0/7 Ex. 4 33 13 17* 0/8Ex. 4 100  −10  22 regression* 1/8 Ex. 5 10 38 50  0/8 Ex. 5 33 35 46 0/8 Ex. 5 100  18 24* 0/8 Mitomycin C 2 mg/kg 15 20* 0/8 (a knownantineoplastic compound)

[0114] The following results were obtained for compounds of Ex.'s 1, 2,4, and 5 tested against HCT-116 tumor xenografts 3X/week for 3 weeks:TABLE 2c Dose Δ MTV % T/C or % Compound (μmol/kg) (mm³) regressionDead/Total Ex. 1 10 360  89  0/8 Ex. 1 33 142  35* 0/8 Ex. 1 100  42 10*0/8 Ex. 2 10 303  75  0/8 Ex. 2 33 225  56* 0/8 Ex. 2 100  102  25* 0/8Ex. 4 10 280  70* 0/8 Ex. 4 33 87 22* 0/8 Ex. 4 100  44 11* 1/8 Ex. 5 10376  93  0/8 Ex. 5 33 270  67* 0/8 Ex. 5 100  111  28* 0/85-fluorouracil 75 mg/kg 65 16* 0/8 (a known antineoplastic compound)

[0115] The following results were obtained for compounds of Ex's 1 and 4tested against PC-3 tumor xenografts 3X/week for 3 weeks: TABLE 2d DoseΔ MTV % T/C or % Compound (μmol/kg) (mm³) regression Dead/Total Ex. 1 101931  87 0/7 Ex. 1 33 718 32 0/8 Ex. 1 100  185  8* 1/8 Ex. 4 10 1722 77 0/8 Ex. 4 33 638 29 0/8 Ex. 4 100  100  4* 0/8 Paclitaxel 15 mg/kg−103  100 regression* 3/8 (a known antineoplastic compound)

[0116] The precise dosage of the compounds of formula I to be employedfor inhibiting tumors depends upon several factors including the host,the nature and the severity of the condition being treated, the mode ofadministration and the particular compound employed. However, ingeneral, satisfactory inhibition of tumors is achieved when a compoundof formula I is administered parenterally, e.g., intraperitoneally,intravenously, intramuscularly, subcutaneously, intratumorally, orrectally, or enterally, e.g., orally, preferably intravenously ororally, more preferably intravenously at a daily dosage of 1-300 mg/kgbody weight or, for most larger primates, a daily dosage of 50-5000,preferably 500-3000 mg. A preferred intravenous daily dosage is 1-75mg/kg body weight or, for most larger primates, a daily dosage of50-1500 mg. A typical intravenous dosage is 20 mg/kg, three to fivetimes a week.

[0117] Usually, a small dose is administered initially and the dosage isgradually increased until the optimal dosage for the host undertreatment is determined. The upper limit of dosage is that imposed byside effects and can be determined by trial for the host being treated.

[0118] The compounds of formula I may be combined with one or morepharmaceutically acceptable carriers and, optionally, one or more otherconventional pharmaceutical adjuvants and administered enterally, e.g.orally, in the form of tablets, capsules, caplets, etc. or parenterally,e.g., intraperitoneally or intravenously, in the form of sterileinjectable solutions or suspensions. The enteral and parenteralcompositions may be prepared by conventional means.

[0119] The infusion solutions according to the present invention arepreferably sterile. This may be readily accomplished, e.g. by filtrationthrough sterile filtration membranes. Aseptic formation of anycomposition in liquid form, the aseptic filling of vials and/orcombining a pharmaceutical composition of the present invention with asuitable diluent under aseptic conditions are well known to the skilledaddressee.

[0120] The compounds of formula I may be formulated into enteral andparenteral pharmaceutical compositions containing an amount of theactive substance that is effective for inhibiting tumors, suchcompositions in unit dosage form and such compositions comprising apharmaceutically acceptable carrier.

[0121] The following examples show representative compounds encompassedby this invention and their synthesis. However, it should be clearlyunderstood that it is for purposes of illustration only.

EXAMPLE 1

[0122] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide

[0123] a) Preparation of3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone.

[0124] α-D-Glucoheptonic γ-lactone (500 g, 2.4 mol) is added into 9 L ofacetone in a 5 gal plastic drum. The mixture is agitated mechanicallyuntil most of the solid dissolved (15-20 min). Iodine (60g, 0.236 mol)is added portionwise into the lactone soln over 5-10 min. The resultingmixture is stirred overnight. A saturated soln of Na₂S₂O₃ (1.3 L) isadded to the iodine soln to quench the reaction. The resulting soln isconcd to about half of its original volume in vacuo, and brine soln (5L) is added. The resulting mixture is extracted with 3×1.2 L EtOAc. Allorganic layers are combined and evaporated to dryness. The solid isslurried with a mixture of ether and hexane (3:7), and filtered. Thefilter cake is washed with Et₂O (50 mL) and air dried, giving 599 g ofthe desired compound as a white powder (86.5%): ¹H NMR (CDCl₃) δ 4.62(m, 1H), 4.50 (m, 1H), 4.35 (m, 2H), 4.07 (m, 1H), 3.93 (m, 1 H), 3.82(dd, 1 H), 3.08 (d, 1H), 1.51 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H), 1.35(s, 3H); ¹³C NMR (CDCl₃) δ 174.4, 109.4, 98.6, 72.8, 71.4, 69.3, 68.4,67.8, 66.7, 28.6, 26.7, 24.6, 19.3.

[0125] b) Preparation of2-O-methyl-3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonicγ-lactone.

[0126] 3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone(719 g, 2.49 mol) is added into 4.5 L of CH₂Cl₂ in a 5 gal plastic drum.The mixture is stirred under N₂. Iodomethane (2500 g, 17.6 mol) is addedimmediately followed by addition of silver(I)oxide (1750 g, 7.58 mol).Water (30 mL) is added to the reaction mixture. Ice bath is used tomaintain the reaction temp at 15-30° C. The reaction is stirred in theabsence of light for 18 h. After diluting the reaction mixture with 1.5L of CH₂Cl₂, the solid is filtered and washed with an additional 2.2 Lof CH₂Cl₂. The undesired solid is discarded and the filtrate isevaporated to dryness. The residue is slurried in Et₂O (1.5 L),filtered, and dried to give 618 g product (82%): ¹H NMR (CDCl₃) δ 4.75(m, 1H), 4.33 (m, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 4.07 (m, 1 H), 3.96(dd, I H), 3.83 (dd, I H), 3.65 (s, 3H), 1.57 (s, 3H), 1.42 (s, 6H),1.35 (s, 3H); ¹³C NMR (CDCl₃) δ 172.5, 109.6, 98.5, 79.0, 73.1, 69.5,68.6, 67.5, 66.9, 59.1, 28.9, 26.9, 24.9, 19.4.

[0127] c) Preparation of2-O-Methyl-3,5-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone.

[0128] 2-O-methyl-3,5:6,7-bis-O-(1-methylethylidene)-α-D-glucoheptonicγ-lactone (618 g, 2.05 mol) is dissolved in 8 L of a mixture of aceticacid and water (1:1) over 30 min. The soln is stirred at ambient tempovernight. The soln is evaporated to dryness in vacuo. The solid isslurried in 3-5 L of hot acetone and filtered. After oven drying at20-30° C., 363 g of the desired compound is obtained (67.6%). ¹HNMR(CDCl₃): δ 4.92 (d,1 H), 4.80 (m,1 H), 4.47 (d, 1H), 4.42 (t, 1H),4.39 (m, 1H), 3.95 (dd, 1H), 3.75 (m, 2H), 3.4 (s, 3H), 2.5 (m, 1H),1.42 (s, 3H), 1.22 (s, 3H).

[0129] d) Preparation of2,4-O-(1-methylethylidene)-5-O-methyl-L-glucuronic γ-lactone.

[0130] 2-O-Methyl-3,5-O-(1-methylethylidene)-α-D-glucoheptonic γ-lactone(200 g, 0.76 mol) is dissolved into a 1:1 mixture of methanol and water(3.6 L). The stirred mixture is cooled in an ice water bath to about 8°C. Solid NalO₄ (213 g, 0.98 mol) is added portionwise. Reaction iscomplete within 40 min as indicated by TLC (silica gel, 5% methanol, 15%EtOAc in CH₂Cl₂). Solid NaCl is added into the reaction mixture tosaturate the methanolic soln. The solid is filtered and washed with 2 LCH₂Cl₂. The filtrate is extracted with 7×500 mL CH₂Cl₂. Combined organiclayers are dried over Na₂SO₄, filtered and concd to a syrup, whichformed a precipitate upon addition of hexane. The solid is filtered andrinsed with Et₂O. A portion of the crude product (50 g) is dissolved in3 L CHCl₃ and heated to reflux. After rotary evaporation of 2.1 L ofCHCl₃ at atmospheric pressure (methanol is driven out of the system bycoevaporation with CHCl₃) the residue is evaporated to dryness. 44 g ofthe desired product is obtained as a solid after drying in vacuoovernight. ¹H NMR (CDCl3): δ 9.60 (s, 1H), 4.78 (m, 1H), 4.42 (s, 2H),4.15 (dd, 1H), 3.65 (s, 3H), 1.58 (s, 3H), 1.55 (s, 3H); ¹³C NMR (CDCl₃)δ 198.8,171.9, 99.0, 78.4, 74.4, 72.9, 68.4, 67.4, 59.2, 28.7,19.0.

[0131] e) Preparation of(6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-O-(1-methylethylidene)-gulo-non-6-enonicacid lactone.

[0132] Into a 2 L round bottom flask, is added CrCl₂ (50 g, 41 mmol ),anhydrous THF (750 mL), and DMF (32 mL). The mixture is stirred under N₂for 1h. A soln of2,4-O-(1-methylethylidene)-5-O-methyl-L-glucuronic-lactone (12 g, 50mmol), 1,1-diiodo-2,2-dimethylpropane (15 mL), and 500 mL of anhydrousTHF is added slowly into the reaction mixture. After the addition, thereaction mixture is stirred at ambient temp for 1.5 h. The reaction isquenched with satd. aq. NH₄Cl. The residue is partitioned withEtOAc/water and chromatographed (5% EtOAc—CH₂Cl₂) to give 9 g (63%) ofthe desired compound as a white crystalline solid: ¹HNMR (CDCl₃) δ 5.82(d, 1H), 5.58 (q, 1H), 4.71 (m, 1H), 4.46 (m, 1H), 4.10 (dd, 1H), 4.0(m, 1H), 3.66 (s, 3H), 1.58 (s, 3H), 1.53 (s, 3H), 1.07 (s, 9H); ¹³C NMR(CDCl₃) δ 172.5, 147.0, 120.2, 98.7, 79.1, 71.9, 70.3, 67.6, 59.2, 33.2,29.3, 19.3.

[0133] f) Preparation of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one

[0134] In a 1 I flask (5R)-5-hydroxy-L-lysine (10 g, 0.040 mol),1-hydroxybenzotriazole hydrate (8.2 g, 0.060 mol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide-HCl (11.6 g, 0.060 mol)are added to 500 ml DMF with stirring. After 0.5 h triethylamine (16.8ml, 0.120 mol) is added. The reaction is stirred at rt for 48 h.Di-tert-butyl dicarbonate (17.6 g, 0.080 mol) and triethylamine (16.8ml, 0.120 mol) are added. Stirring is continued for 16 h. The reactionmixture is filtered to remove triethylamine-HCl and the solvent isremoved by rotary evaporation under high vacuum to give a thick oil. Theoil is dissolved in 150 ml CH₂Cl₂ and applied to a silica gel column(150 g, 40×250 mm). The column is eluted with 3% methanol in CH₂Cl₂ togive the crude product as a solid. The crude solid is dissolved in 120ml hot CH₂Cl₂ and cooled to −20° C. for 1 h. The resulting solid isfiltered and washed with 50 ml CH₂Cl₂. The combined filtrates areevaporated to dryness. CH₂Cl₂ (40 ml) is added to this residue and theresulting slurry is stirred for 0.5 h at rt. The slurry is filtered andthe solid washed with 25 ml CH₂Cl₂. The solids are combined to give 5.57g of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one. 300MHz ¹H NMR (DMSO) δ 7.42 (1 H, t, J =5.1 Hz), 6.38 (1 H, d, J =6.6 Hz),4.60 (1 H, d, J =4.2 Hz), 4.07 (1 H,m), 3.74 (1 H, m), 3.32 (1 H, m),3.03 (1 H, m), 1.8-1.5 (4 H, m), 1.39 (9 H, s).

[0135] g) Preparation of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one.

[0136] Triethylamine (8.4 mL, 60 mmol) is added to a solution ofcyclohexanecarbonyl chloride (6.3g, 43.0 mmol), (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (7.0g, 28.7 mmol) and 100 mL of CH₂Cl₂ at 5° C. The reaction mixture isstirred at room temp. overnight. The reaction mixture is thenpartitioned with water, and the organic layer is dried (Na₂SO₄), andconcentrated with rotary evaporation. The resulting residue ischromatographed (5% EtOAc—CH₂Cl₂) to give 10.1 g (99.5% of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-oneas a white solid: ¹H NMR (CDCl₃): δ 5.89 (d, J=5.27 Hz, 1H), 5.65 (t,J=4.90 Hz, 1H), 4.89 (s, 1H), 4.30 (q, J=4.14 Hz, 1H), 3.49 (m, 2H),2.31 (tt, J=10.92 Hz and 3.39 Hz, 1H), 2.13 (d, J=14.32 Hz, 1H), 1.98(d, J=13.56 Hz, 2H), 1.88 (d, J=14.31 Hz, 2H), 1.75 (d, J=11.30 Hz, 2H),1.66 (s, 2H), 1.45 (s, 9H), 1.30 (m, 5H).

[0137] h) Preparation of (3S,6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one.

[0138] To a solution of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one(10g, 28.2 mmol) in 40 mL of CH₂Cl₂ is added TFA (25 mL) at room temp.,and the reaction solution is stirred at room temp. for 1 hr, then concdvia rotary evaporation (bath temp<20° C.). The residue is diluted withCH₂Cl₂ (100 mL), and washed with NH₄OH (10 mL) and then water (2×20 mL)and dried (Na₂SO₄). The reaction mixture is adsorbed on silica andchromatographed (5% methanol-CH₂Cl₂) to give 6.0 g (85.0%) of (3S,6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one as awhite solid: ¹H NMR (CDCl₃): δ 6.91 (s, 1H), 4.91 (s, 1H), 4.39 (s, 2H),3.87 (d, J=9.80 Hz, 1H), 3.48 (t, J=6.02 Hz, 1H), 3.43 (dd, J=15.45 Hzand 4.90 Hz, 1H), 2.30 (tt, J=10.92 Hz and 3.39 Hz, 1H), 2.13 (m, 1H),1.91 (m, 4H), 1.73 (m, 2H), 1.65 (m, 1H), 1.40 (q, J=11.68 Hz, 4H), 1.24(m, 2H).

[0139] i) Preparation of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0140] A soln consisting of(6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-O-(1-methyl-ethylidene)-gulo-non-6-enonicacid lactone (1.0 g, 3.5 mmol), (3S,6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)osy-2H-azepin-2-one (2.5 g,9.8 mmol), and i-PrOH (4 mL) is stirred at reflux for 24 h. The reactionmixture is adsorbed on silica and chromatographed (2% methanol—CH₂Cl₂)to give 1.85 g (97%) of the desired compound as a white solid: ¹H NMR(CDCl₃) δ 7.58 (d, J=6.341 Hz, 1H), 5.80 (t, J=7.68 Hz, 1H), 5.78 (d,J=15.83 Hz, 1H), 5.53 (dd, J=15.83 Hz and 6.78 Hz 1H), 4.92 (sd, J=3.39Hz, 1H), 4.60 (dd, J=0.42 Hz and 7.4 Hz, 1H), 4.28 (d, J=6.79 Hz, 1H),4.07 (dd, J=7.54 Hz and 1.13 Hz, 1H), 3.90 (d, J=7.15 Hz, 1H), 3.52 (dd,J=12.05 Hz and 7.91 Hz, 2H), 3.48 (s, 3H), 2.82 (d, J=9.04 Hz, 1H), 2.32(m, 1H), 2.12(m,1H), 2.00 (m, 2H), 1.89 (d, J=13.06 Hz, 2H), 1.75 (m,4H), 1.66 (m, 1H), 1.46 (d, J=4.90 Hz, 6H),1.38 (m, 2H), 1.26 (m, 3H),1.03 (s. 9H).

[0141] i′) Alternative preparation of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0142] (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-one(300 g, 846 mmol) is added portionwise to a stirred solution of ethylacetate (3 L) and HCl gas (225 g, 6.2 mol) at room temp. The reaction isstirred at room temp. for 6 h. The resulting precipitate is filtered andthe solid is washed with ethyl acetate (1.2 L). The solid is dried togive 246 g (98%) of (3S,6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-oneHClwhich is used directly in the next step. A soln consisting of(6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-0-(1-methylethylidene)-gulo-non-6-enoicacid lactone (100 g, 352 mmol), (3S,6R)-3-aminohexahydro-6-(cyclohexanecarbonyl)oxy-2H-azepin-2-oneHCl(112.5g, 387 mmol), sodium 2-ethylhexanoate (116 g, 700 mmol), andtetrahydrofuran (1.75 L) is stirred at room temp for 20 h. Water (350mL) is then added to the mixture. After stirring for an additional 30min, heptane (3.5 L) is added. The mixture is then stirred for 3 h, thencooled to 2° C. and then stirred for an additional 2 h. The mixture isfiltered through a polypropylene filter. The solid that remains iswashed with water (200 mL) and heptane (800 mL). The solid is then driedto give 166 g (88%) of the desired compound as a white solid.

[0143] j) Preparation of the Title Compound.

[0144] (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide(3.8 g, 7.1 mmol) is added in one portion to a stirred soln of TFA (10mL), THF (10 mL), and water (5 mL) at 0° C. The reaction is stirred atthis temp for 30 min, concd via rotary evaporation (bath temp<20° C.),mixed with saturated NH₄HCO₃ (5 mL), and stirred for 15 min. The mixtureis concd in vacuo and chromatographed (2% methanol—CH₂Cl₂) to give awhite solid with H₂O solubility of 3.7 mg/mL. This material is furtherpurified using preparative hplc (reverse phase eluted with 90%CH₃CN—water) to give 2.9 g (82.4%) of the title compound as a whitesolid, mp 79-80° C.; ¹H NMR (CDCl₃) δ 8.00 (d, J=6.30 Hz, 1 H), 5.98 (t,J=5.52 Hz, 1H), 5.83 (d, J=15.77 Hz, 1H), 5.42 (dd, J=15.76 Hz and 7.25Hz 1H), 4.93 (m, 1H), 5.56 (m, 1H), 4.22 (m, 2H), 3.82 (m, 2H), 3.81 (t,J=5.99 Hz, 1H), 3.55 (s,3H), 3.49 (dd, J=15.77 Hz and 5.36 Hz, 1H), 3.30(d, J=7.25 Hz, 1H), 3.10 (s, 1H), 2.31 (m, 1H), 2.16 (d, J=11.19 Hz,1H), 2.00 (m,2H), 1.88 (m, 3H), 1.76 (s, 2H), 1.65 (d, J=0.87 Hz, 1H),1.42 (m, 2H), 1.25 (m, 4H), 1.02 (s. 9H); ¹³C NMR (CDCl₃) δ 175.19,174.11, 172.12, 145.74, 123.20, 81.10, 74.50, 72.75, 72.45, 66.74,59.93, 51.66, 43.31, 43.22, 33.03, 31.96, 29.43, 29.07, 29.00, 25.70,25.65, 25.39, 25.36.

EXAMPLE 2

[0145] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclopentylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0146] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of cyclopentanecarbonyl chloride, (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclopentanecarbonyl)oxy-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1 h), 1 i) and the laststep of Example 1, the title compound is obtained. H₂O solubility=18mg/mL; mp 75-76° C.; ¹H NMR (DMSO): δ 7.81 (d, J=6.47 Hz, 1H), 7.76 (t,J=6.07 Hz, 1H), 5.64 (d, J=15.77 Hz,1 H), 5.34 (dd, J=15.76 Hz and 2.84Hz, 1 H), 4.80 (s, 1 H), 4.57 (d, J=4.73 Hz,1 H), 4.48 (d, J=6.94 Hz, 1H), 4.45 (m, 1 H), 4.36 (d, J=5.83 Hz, 1 H), 3.98 (m, 1 H), 3.71 (d,J=6.94 Hz I H), 3.57 (td, J=6.78 Hz and 2.68 Hz, 1 H), 3.52 (dd, J=15.61Hz and 4.57 Hz, 1H), 3.34 (td, 6.15 Hz and 2.84 Hz, 1H), 3.32 (s, 3H),3.23 (m, 1H), 2.72 (m, 1H), 2.50 (m, 1H), 1.93 (m, 2H), 1.80 (m, 2H),1.73 (m, 3H), 1.61 (m, 2H), 1.53 (m, 2H), 0.98 (s, 9H); ¹³C NMR (DMSO):δ 174.75, 173.56, 169.73,141.69, 125.32, 81.60, 72.82, 72.54, 70.80,67.20, 57.31,50.95, 43.21, 32.44, 31.31, 29.45, 29.38, 25.30, 25.23.

EXAMPLE 3

[0147] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cycloheptylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0148] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of: cyclo-heptanecarboxylic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cycloheptane-carbonyl)oxy-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1h), 1i) and the laststep of Example 1, the title compound is obtained: mp 84-86° C.; ¹H NMR(CDCl₃): δ 8.00 (d, J=6.30 Hz, 1H), 5.93 (t, J=5.52 Hz, 1H), 5.83 (d,J=15.77 Hz, 1H), 5.42 (dd, J=15.7 Hz and 7.26 Hz, 1 H), 4.93 (m, 1 H),4.55 (dd, J=9.46 Hz and 6.31 Hz, 1 H), 4.23 (m, 2H), 3.82 (m,2H), 3.61(t, J=6.14 Hz, 1 H), 3.57 (m, 1 H), 3.55 (s, 3H), 3.49 (dd, J=15.60 Hzand 5.20 Hz, 1 H), 3.29 (d, J=7.25 Hz,1H), 3.10 (s, 1H), 2.50 (m, 1H),2.17 (m, 1H), 1.95 (m, 4H), 1.70 (m, 1H), 1.65 (m, 2H), 1.55 (m, 4H),1.47 (m, 4H), 1.02 (s, 9H); ¹³C NMR (CDCl₃): δ 176.17, 174.07, 172.14,145.75, 123.20, 81.08, 74.51, 72.76, 72.44, 66.79, 59.95, 51.67, 45.07,43.36, 33.03, 31.95, 30.91, 30.84, 29.43, 28.24, 28.21, 26.26, 25.73.

EXAMPLE 4

[0149] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl]non-6-enamide.

[0150] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of 3-phenylpropionyl chloride, (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-3-phenylpropoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1 h),1 i) and the laststep of Example 1, the title compound is obtained: H₂O solubility=0.8mg/mL; mp 75-77° C.; ¹H NMR (CDCl₃) δ 7.96 (d, J=6.15 Hz,1 H), 7.31 (t,J=7.25 Hz,2H), 7.23 (t, J=7.57 Hz, 1H), 7.20 (d, J=7.41 Hz, 2H), 5.82(d, J=15.76 Hz,1 H), 5.62 (s, 1H), 5.41 (dd, J=15.76 Hz and 7.09 Hz,1H), 4.92 (s, 1H), 4.49 (dd, J=9.46 Hz and 6.31 Hz, 1 H), 4.22 (m, 2H),3.80 (m, 2H), 3.60 (s, 1 H), 3.52 (s, 3H), 3.37 (m,3H), 3.17 (s, 1H),2.95 (t, J=7.57 Hz, 2H), 2.67 (t, J=7.72 Hz, 2H), 2.06 (d, J=11.98 Hz,1H), 1.96 (t, J=12.77 Hz, 1H), 1.88 (s, 1H), 1.70 (m, 1H), 1.02 (s, 9H);¹³C NMR (CDCl₃): δ 173.96, 172.05, 172.00 145.68, 140.08, 128.61,128.42, 126.52, 123.21, 81.18, 74.46, 72.69, 72.50, 67.14, 59.83, 51.49,43.22, 35.78, 33.02, 31.79, 31.07, 29.43, 25.58.

EXAMPLE 5

[0151] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-3-[3-pyridyl]propoxy)-2H-azepin-3-yl]non-6-enamide.

[0152] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of: 3-(pyridyl)propionic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-3-[3-pyridyl]propoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1 h), 1 i) and the laststep of Example 1, the title compound is obtained. ¹H NMR (CDCl₃) δ 8.46(s, 2H), 7.97 (d, J=6.2 Hz, 1H), 7.53 (m, 1H), 7.23 (m, 1H), 5.88 (t,J=6.0 Hz, 1H), 5.81 (d, J=15.6 Hz, 1H), 5.4 (dd, J=15.6 and 7.3 Hz, 1H),4.93 (m, 1H), 4.27 (s, 1H), 4.23-4.19 (m, 1H), 3.8 (m, 2H), 3.59 (d,J=5.2 Hz, 1H), 3.52 (s, 3H), 3.48 (m, 2H), 3.28 (s, 1H), 3.19 (s, 1H),2.95 (t, J=7.3 Hz, 2H), 2.67 (t, J=7.3, 2H), 2.1-1.67 (m, 6H), 1.0 (s,9H); ¹³C NMR (CDCl₃) δ 174.0, 172.0,171.5, 149.7, 148.0, 145.7, 136.0,135.5, 123.6,123.2, 81.2, 74.5, 72.7, 72.5, 67.6, 59.8, 51.6, 43.3,35.2, 33.0, 31.8, 29.4, 28.0, 25.5. HPLC: C-18 Novapac, 4.6×250 mm, 1.5mL/min; solvent system: 25% MeCN/75% H₂O [isocratic]; retentiontime=13.7 min.

EXAMPLE 6

[0153] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylmethylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0154] Following essentially the procedure of Example 1 g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of:

[0155] cyclohexylacetic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(cyclohexyl-methylcarbonyl)oxy-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1 h),1 i) and the laststep of Example 1, the title compound is obtained. ¹H NMR (CDCl₃) δ 7.98(d, J=6.2, 1H), 5.83-5.7 (m, 1H), 5.80 (d, J=15.6 Hz, 1H), 4.94 (m, 1H),4.52 (m, 1H), 4.2 (m, 2H), 3.78 (m, 2H), 3.6-3.48 (m, 3H), 3.52 (s, 3H),3.23 (d, J=7.3 Hz,1 H), 3.06 (m,1 H), 2.80 (d, J=7 Hz, 2H), 2.13-1.63(m, 12H), 1.30-0.85 (m, 5H), 1.0 (s, 9H); ¹³C NMR (CDCl₃) δ 174.0,172.3, 172.2, 145.7, 123.3, 81.1, 74.5, 72.8, 72.5, 67.0, 60.0, 51.7,43.5, 42.1, 35.0, 33.0, 32.0, 29.5, 26.1, 26.0, 25.7. HPLC: C-18Novapac, 4.6×250 mm, 1.5 mL/min; solvent system: 40% MeCN/60% H₂O[isocratic]; retention time =11.5 min.

EXAMPLE 7

[0156] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-2-phenylethoxy)-2H-azepin-3-yl]non-6-enamide.

[0157] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of:

[0158] phenylacetic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride and 4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-2-phenylethoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1 g), andfollowing essentially the procedure of Example 1h), 1i) and the laststep of Example 1, the title compound is obtained. ¹H NMR (CDCl₃) δ 7.96(d, J=6.2, 1 H), 7.28 (m, 5H), 5.80 (d, J=15.8, 1H), 5.68 (t, J=6.4 Hz,1H), 5.39 (dd, J=15.8 and 7.3 Hz, 1H), 4.93 (m, 1H), 4.53-4.47 (m, 1H),4.22-4.18 (m, 2H), 3.60-3.56 (m, 2H), 3.52 (s, 3H), 3.48-3.38 (m, 2H),3.27 (d, J=6.6 Hz, 1H), 3.08 (s, 1H), 2.15-1.67 (m, 5H), 1.0 (s, 9H);¹³C NMR (CDCl₃) δ 173.9, 172.1, 170.8, 145.8,133.6, 129.2, 128.8, 127.4,123.2, 81.1, 74.5, 72.7, 72.4, 67.6, 59.9, 51.6, 43.2, 41.5, 33.0, 31.8,29.4, 25.5. HPLC: C-18 Novapac, 4.6×250 mm, 1.5 mL/min; solvent system:10-100% MeCN/H₂O [>20 min gradient]; retention time=12.2 min.

EXAMPLE 8

[0159] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-2-[3,4-dichlorophenyl]ethoxy)-2H-azepin-3-yl]non-6-enamide.

[0160] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of: 3,4-dichlorophenylacetic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-2-[3,4-dichlorophenyl]ethoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1h), 1i) and the laststep of Example 1, the title compound is obtained; mp 132-136° C.; ¹HNMR (CDCl₃) δ 8.00 (d, J=6 Hz, 1H), 7.51 (s, 1H), 7.41 (m, 2H), 7.16(dd, J=3 Hz and 9 Hz, 1H), 5.77 (d, J=16 Hz, 1H), 5.42 (dd, J=8 Hz and16 Hz, 1H), 4.93 (d, J=3 Hz, 1H), 4.55 (q, J=6 Hz, 1H), 4.19 (m, 1H),3.83 (m, 3H), 3.63 (d, J=6 Hz, 3H), 3.48 (m, 6H), 3.39 (s, 1H), 2.13 (d,J=16 Hz, 1H), 2.00 (m, 2H), 1.77 (q, J=12 Hz, 1H), 1.03 (s, 9H); ¹³C NMR(CDCl₃) δ 169.1, 144.2, 133.5, 131.5, 130.9, 130.8, 129.8, 128.5, 123.4,81.3, 73.6, 72.2, 71.7, 67.6, 58.4, 50.8, 49.3, 42.0, 32.3, 31.1, 30.7,28.8, 24.8.

EXAMPLE 9

[0161] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-2-[4-methoxyphenyl]ethoxy)-2H-azepin-3-yl]non-6-enamide.

[0162] a) Preparation of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-t-butyl-dimethylsilyloxy-2H-azepin-2-one.

[0163] (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one(25g, 102 mmol), tert-butyldimethylsilyl chloride (23.16g, 153 mmol),and imidazole (10.45g, 153 mmol) are combined with 60 mL of DMF. Thereaction is stirred at room temperature overnight. The mixture isdiluted with 1 L of water. The resulting mixture is extracted with a 1:1(2×200 mL) mixture of ethyl acetate and hexane. All organic layers arecombined, washed with brine solution, dried with NaSO₄, andconcentrated. The residue is purified by recrystallization with ethylacetate/hexane to give 28.5g (78%) of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyidimethylsilyloxy-2H-azepin-2-oneas a white solid, mp 65-66° C.; ¹H NMR (CDCl₃) δ 5.86 (d, J=6 Hz, 1H),5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H), 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004(s, 6H).

[0164] b) Preparation of (3S,6R)-3-aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one.

[0165] (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one(8.0g, 22 mmol) is dissolved in 40 mL of CH₂Cl₂ and cooled to −78° C.Trimethylsilyl iodide (3.5 mL, 24.5 mmol) is added slowly. The mixtureis allowed to react at −78° C. for 30 min. The reaction is warmed to 0°C. and stirred for 15 min. The solution turned yellow. The reaction isquenched with NH₄HCO₃ (3.43g, 44 mmol) dissolved in 30 mL of CH₃OH, and15 mL water. The mixture is concentrated and chromatographed with 95:5mixture of CH₂Cl₂ and methanol to yield 5.45g (96%) of (3S,6R)-3-aminohexahydro-6-tert-butyl-dimethylsilyloxy-2H-azepin-2-one as awhite solid: ¹H NMR (CDCl₃) δ 5.61 (s, 1H), 3.88 (s, 1H), 3.42 (d, J=8Hz, 1 H), 3.32(dd, J=6 Hz and 16 Hz, 1 H), 3.06 (m, 1 H), 1.87 (m, 2H),1.76 (m, 1H), 1.65 (s, 3H), 0.83 (s, 9H), 0.001 (s, 6H).

[0166] c) Preparation of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-tert-butyldimethylsilyloxy-2H-azepin-3-yl]non-6-enamide.

[0167] (3S,6R)-3-aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one(5.45g, 21 mmol),(6E)-6,7,8,9-tetradeoxy-8,8-dimethyl-2-O-methyl-3,5-O-(1-methylethylidene)-gulo-non-6enonicacid lactone (3.0 g, 11 mmol), and diisopropylethylamine (4.6 mL, 26mmol) are combined with 30 mL of isopropanol at room temperature. Themixture is heated to reflux overnight. The mixture is cooled to roomtemperature and concentrated. The residue is chromatographed with 98:2mixture of CH₂Cl₂ and methanol to yield 2.53 g (42%) of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-tert-butyidimethylsilyloxy-2H-azepin-3-yl]non-6-enamide(42%) as a white solid: ¹H NMR (CDCl₃) δ 7.53 (d, J=6 Hz, 1 H), 5.72 (d,J=16 Hz, 1 H), 5.47 (dd, J=6 Hz and 16 Hz, 1H), 4.47 (m, 1H), 4.22 (d,J=6 Hz, 1H), 4.03 (d, J=8 Hz, 1H), 3.91 (m, 1H), 3.82 (d, J=7 Hz, 1 H),3.48 (d, J=9 Hz, 1 H), 3.43 (s, 3H), 3.35 (d, J=6 Hz, 1 H), 3.09 (m.1H), 2.77 (d, J=9 Hz, 1 H), 1.83 (m, 2H), 1.77 (m, 2H), 1.41 (d, J=6 Hz,6H), 0.97 (s, 9H), 0.83 (s, 9H), 0.005 (s, 6H); ¹³C NMR (CDCl₃) δ 172.2,169.6, 148.3, 145.3, 121.5, 108.8, 99.6, 81.4, 80.5, 79.2, 78.2, 74.4,73.1, 69.1, 67.9, 65.8, 59.2, 56.4, 51.7, 36.8, 36.5, 33.1, 29.6, 29.4,19.1.

[0168] d) Preparation of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-hydroxy-2H-azepin-3-yl]non-6-enamide.

[0169] (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-tert-butydimethylsilyloxy-2H-azepin-3-yl]non-6-enamide(2.5 g, 4.6 mmol) is dissolved in 30 mL of THF. 1.0M in THF solution oftetrabutylammonium fluoride (13.8 mL, 14 mmol) is added at roomtemperature and stirred for 3 hrs. The mixture is concentrated andchromatographed with 95:5 mixture of CH₂Cl₂ and methanol to give 1.8g(91%) of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-hydroxy-2H-azepin-3-yl]non-6-enamide as a whitesolid: ¹H NMR (CDCl₃) δ 7.61 (d, J=6 Hz, 1 H), 6.45 (t, J=6 Hz,1 H),5.77 (d, J=6 Hz, 1H), 5.52 (dd, J=6 Hz, and 16 Hz, 1H), 4.56 (m, 1H),4.28 (d, J=6 Hz, 1H), 4.06 (d, J=8 Hz, 1H), 4.00 (m, 1 H), 3.91 (d, J=8Hz,1 H), 3.54 (m, 1 H), 3.47 (s, 3H), 3.35 (m, 2H), 3.08 (d, J=8 Hz,1H), 2.76 (d, J=6 Hz, 1), 2.02 (m, 2H), 1.83 (m, 2H), 1.45 (s, 6H), 1.03(s, 9H); ¹³C NMR (CDCl₃) δ 175.1, 169.7, 145.3, 121.5, 99.7, 83.1, 80.6,74.5, 73.2, 65.8, 64.6, 59.1, 51.8, 45.9, 34.5, 33.1, 29.5, 29.3, 25.1,19.1, 13.7.

[0170] e) Preparation of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-2-[4-methoxyphenyl]ethoxy)-2H-azapan-3-yl]non-6-enamide.

[0171] 4-Methoxyphenylacetic acid (0.35g, 2.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbo-diimide hydrochloride (0.42g, 2.1mmol), and DMAP (0.17g, 1.4 mmol) are combined with 30 mL of CH₂Cl₂ andstirred at room temperature for 30 min. (2R, 3R, 4S, 5R,6E)-3,5-(methyl-ethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-hydroxy-2H-azepin-3-yl]non-6-enamide (0.6g, 1.4mmol) is added to the mixture and stirred overnight at room temperature.The mixture is concentrated. The residue is chromato-graphed with 98:2mixture of CH₂Cl₂ and methanol to give 0.644g (80%) of (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-2-[4-methoxyphenyl]ethoxy)-2H-azapan-3-yl]non-6-enamideas a white solid: ¹H NMR (CDCl₃) δ 7.56 (d, J=6 Hz, 1H), 7.18 (d, J=8Hz, 2H), 6.86 (d, J=8 Hz, 2H), 5.78 (d, J=16 Hz,1 H), 5.62 (t, J=6 Hz,1H), 5.52 (dd, J=6 Hz and 16 Hz, 1 H), 4.93 (s, 1 H), 4.58 (m, 1H), 4.28(d, J=12 Hz, 1H), 4.06 (d, J=8 Hz, 1H), 3.88 (d, J=7 Hz, 1H), 3.80 (s,3H), 3.56 (s, 2H), 3.48 (s, 5H), 2.82 (d, J=11 Hz, 1 H), 2.05 (m, 3H),1.71 (s, 2H), 1.42 (d, J=6 Hz, 6H), 1.03 (s, 9H); ¹³C NMR (CDCl₃) δ174.3, 171.1, 169.7, 158.9, 145.3, 130.2, 125.7, 121.6, 114.2, 99.7,80.6, 74.5, 73.3, 67.7, 65.8, 59.3, 55.3, 51.7, 43.3, 40.6, 33.1, 31.8,31.4, 29.4, 25.8, 19.1.

[0172] f) Preparation of the Title Compound.

[0173] 30 mL solution of (3:3:2) TFA, THF, and water at 0° C. is addedto a flask containing (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-2-[4-methoxyphenyl]ethoxy)-2H-azapan-3-yl]non-6-enamide(0.64g, 1.1 mmol). The mixture is allow to react at 0° C. for 30 min.The mixture is evaporated to dryness under high vacuum. The residue isneutralized with a solution NH₄HCO₃ (1.2g in 20 mL of water). Themixture is evaporated to dryness under high vacuum. The residue ischromatographed with a 95:5 mixture of CH₂Cl₂ and methanol to yield0.35g (60%) of the title compound as a white solid: ¹H NMR (CDCl₃) δ7.98 (d, J=6 Hz, 1H), 7.18 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 2H), 5.83(d, J=16 Hz, 1H), 5.72 (t, J=6 Hz, 1H), 5.42 (dd, J=8 Hz and 16 Hz,1 H),4.93 (d, J=3 Hz,1 H), 4.53 (m,1 H), 4.23 (t, J=6 Hz, 2H), 3.81 (m, 2H),3.80 (s, 3H), 3.61 (t, J=5 Hz,1 H), 3.57 (s, 2H), 3.54 (s, 3H), 3.47(m,1 H), 3.30 (d, J=7 Hz, 1H), 3.12 (s, 1H), 2.16 (d, J=16 Hz, 1H), 1.99(m, 2H), 1.82 (m, 1H), 1.72 (s, 1H), 1.04 (s, 9H); 13C NMR (CDCl₃) δ173.8, 172.2, 171.1,158.9,145.8, 130.2,125.6,123.2, 114.2, 81.0, 74.5,72.8, 72.4, 67.5, 60.0, 55.3, 51.6, 43.2, 40.6, 33.0, 31.8, 31.3, 29.4,25.6.

EXAMPLE 10

[0174] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-([4-n-decyloxyphenyl]carbonyl)oxy-2H-azepin-3-yl]non-6-enamide.Following essentially the procedure of Example 9e) and using in place of4-methoxy-phenylacetic acid, an approximately equivalent amount of4-decyloxybenzoic acid, (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-([4-n-decyloxyphenyl]carbonyl)oxy-2H-azepin-3-yl]non-6-enamideis obtained. Employing the compound above in place of compound 9e), andfollowing essentially the procedure of the last step of Example 9, thetitle compound is obtained as a solid with mp 70-74° C.; ¹H NMR (CDCl₃)δ 8.06 (d, J=6 Hz, 1 H), 7.96 (d, J=9 Hz, 2H), 6.90 (d, J=9 Hz, 2H),6.05 (t, J=6 Hz,1 H), 5.80 (d, J=15 Hz,1 H), 5.44 (dd, J=7 Hz and 15 Hz,1H), 5.20 (m, 1H), 4.63 (m, 1H), 4.25 (t, J=6 Hz, 1H), 4.02 (t, J=6 Hz,2H), 3.84 (dd, J=7 Hz and 13 Hz, 2H), 3.69 (m, 1H), 3.62 (m, 2H), 3.38(d, J=5 Hz, 1H), 3.56 (s, 3H), 3.33 (s, 1H), 3.15 (s, 1H), 2.32 (d, J=12Hz, 1H), 2.13 (t, J=12 Hz, 1H), 2.01 (m, 2H), 1.82 (m, 2H), 1.48 (m,2H), 1.30 (m, 12H), 1.05 (s, 9H), 0.94 (t, J=6 Hz, 3H); 13C NMR (CDCl₃)δ 174.1, 172.1, 165.2,163.4, 145.7, 131.7, 123.2,121.6,114.2, 81.1,74.5,72.7,72.4, 68.3, 67.2, 59.9, 51.7, 43.6, 33.0, 32.1, 31.9, 29.5, 29.4,29.3, 29.2, 29.0, 25.9, 25.9, 22.6,14.1.

EXAMPLE 11

[0175] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-3-phenyl-2-propenoxy)-2H-azepin-3-yl]non-6-enamide.

[0176] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of cinnamoyl chloride, (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-3-phenyl-2-propenoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1h),1i) and the last stepof Example 1, the title compound is obtained as a solid, mp 83-85° C.;¹H NMR (DMSO): δ 8.03 (m, 1H), 7.71 (d, J =16 Hz, 1H), 7.54 (m, 2H),7.41 (m, 2H), 6.45 (d, J=16 Hz, 1H), 5.97 (m, 1H), 5.81 (d, J =16 Hz,1H), 5.45 (dd, J =16 and 8 Hz, 1H), 5.09 (m, 1H), 4.58 (m, 1H), 4.22 (m,2H), 3.81 (m, 2H), 3.62 (m, 4H), 3.54 (s, 3H), 3.30 (d, J=8 Hz, 1H),3.10 (s, 1H), 2.25 (m, 1H), 2.00 (m, 3H), 1.02 (s, 9H); ¹³C NMR (DMSO):δ 174.10, 172.15, 166.01, 145.91, 145.75, 134.03, 130.70,129.00, 128.22,123.20,117.34, 81.10, 74.50, 72.76, 72.46, 67.29, 59.93, 51.67, 43.51,33.03, 32.00, 29.43, 25.75.

EXAMPLE 12

[0177] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-([4-n-decylphenyl]carbonyl)oxy-2H-azepin-3-yl]non-6-enamide.

[0178] Following essentially the procedure of Example 9e) and using inplace of 4-methoxy-phenylacetic acid, an approximately equivalent amountof 4-decylbenzoic acid, (2R, 3R, 4S, 5R,6E)-3,5-(methylethylidene)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-([4-n-decylphenyl]carbonyl)oxy-2H-azepin-3-yl]non-6-enamideis obtained. Employing the compound above in place of compound 9e), andfollowing essentially the procedure of the last step of Example 9, thetitle compound is obtained: mp 60-64° C.; ¹H NMR (CDCl₃) δ 8.06 (d, J=6Hz, 1H), 7.94 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 6.10 (t, J=7 Hz,1H), 5.85 (d, J=16 Hz, 1H), 5.45 (dd, J=8 Hz and 16 Hz, 1H), 5.22 (d,J=3 Hz, 1 H), 4.64 (dd, J=6 Hz and 8 Hz, 1 H), 4.25 (t, J=6 Hz, 2H),3.84 (dd, J=6 Hz and 11 Hz, 2H), 3.69 (t, J=7 Hz, 1 H), 3.63 (dd, J=5 Hzand 8 Hz,2H), 3.56 (s, 3H), 2.68 (t, J=8 Hz, 2H), 2.34 (d, J=13 Hz, 1H),2.14 (t, J=12 Hz, 1H), 2.04 (t, J=11 Hz, 1H), 1.96 (t, J=3 Hz, 1H), 1.63(m, 2H), 1.32 (m, 18H), 1.82 (m, 2H), 1.05 (s, 9H), 0.90 (t, J=7 Hz,3H); ¹³C NMR (CDCl₃) δ 174.1, 172.1, 165.5, 149.3, 145.7, 129.7, 128.6,127.0, 123.2, 81.1, 74.5, 72.7, 72.4, 67.4, 59.9, 51.7, 43.5, 36.0,33.0, 32.1, 31.9, 31.1, 29.6, 29.5, 29.4, 29.3, 29.2, 25.9, 22.6, 14.1.

EXAMPLE 13

[0179] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-3-[3-thiophenyl]ethoxy)-2H-azepin-3-yl]non-6-enamide.

[0180] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of: 3-thiopheneacetic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-3-[3-thiophenyl]ethoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1 h),1 i) and the laststep of Example 1, the title compound is obtained: hplc (C-18 Novapac,4.6×250 mm, 1.5 mL/min) solvent system: 35% MeCN/65% H₂O [isocratic];Retention Time =7.89 min. ¹H NMR (CDCl₃) δ 7.97 (d, J=6 Hz, 1H), 7.30(m, 1H), 7.14 (m, 1H), 7.00 (m, 1H), 5.83 (m, 1H), 5.81 (d, J=16 Hz,1H), 5.40 (dd, J=7 Hz and 16 Hz, 1H), 4.90 (m, 1H), 4.45 (m, 1H), 4.15(m, 1H), 3.75 (m, 2H), 3.66 (s, 2H), 3.57 (s, 3H), 3.40 (m, 2H), 3.32(d, J=7 Hz, 1H), 3.12 (s, 1H), 1.7 (m, 4H), 1.01 (s, 9H); ¹³C NMR(CDCl₃) δ 174.0, 172.1, 170.3, 145.7, 133.1, 126.2, 123.3, 123.1, 81.2,74.5, 72.8, 72.5, 67.8, 59.9, 51.6, 43.2, 36.0, 33.0, 31.8, 29.5, 25.6.

EXAMPLE 14

[0181] (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-3-[3-indolyl]ethoxy)-2H-azepin-3-yl]non-6-enamide.

[0182] Following essentially the procedure of Example 1g) and using inplace of cyclohexane-carbonyl chloride, an approximately equivalentamount of a mixture consisting of: 3-indoleacetic acid,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and4-dimethylaminopyridine; (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-(1-oxo-3-[3-indolyl]ethoxy)-2H-azepin-2-oneis obtained. Employing the compound above in place of compound 1g), andfollowing essentially the procedure of Example 1h), 1i) and the laststep of Example 1, the title compound is obtained: hplc (C-18 Novapac,4.6×250 mm, 1.5 mL/min) solvent system: 35% MeCN/65% H₂O [isocratic];retention time 32 9.2 min. ¹H NMR (CDCl₃) δ 8.47 (s, 1 H), 7.90 (d, J=6Hz, 1 H), 7.55 (d, J=8 Hz, 1 H), 7.36 (d, J=8 Hz, 1H), 7.20-7.05 (m,3H), 5.81 (d, J=16 Hz, 1H), 5.75 (m, 1H), 5.37 (dd, J=8 Hz and 16 Hz, 1H), 4.8 (m,1 H), 4.45-4.30 (m, 2H), 4.25-4.15 (m, 1 H), 3.9-3.7 (m, 4H),3.65-3.55 (m, 1H), 3.50 (s, 3H), 3.45-3.30 (m, 1H), 3.25-3.10 (m, 2H),2.15-2.00 (m, 1H), 2.00-1.60 (m, 4H), 0.99 (s, 9H); ¹³C NMR (CDCl₃) δ173.9, 171.9, 145.7, 136.2, 127.1, 123.3, 123.3, 122.3, 119.8, 118.6,111.5, 108.0, 81.6, 74.4, 72.7, 72.6, 67.5, 59.7, 51.5, 43.1, 33.0,31.8, 31.6, 29.5, 25.6.

EXAMPLE 15

[0183] Infusion

[0184] The compound of Example 1 (15 mg) is dissolved in 98-100%propylene glycol (1.0 ml). The solution is sterile filtered through a0.22 microns pore size filter and charged to 1 ml ampoules. The filledampoules are used for storage and shipment. The filled ampoules arestable for a period of at least 12 months at a temperature of 2 to 8° C.Prior to intravenous administration, the contents of an ampoule areadded to 250 to 1000 ml of a 5% glucose solution in water-for-injection.The intravenous solution thus formed is stable for a period of 8 hoursat room temperature.

[0185] Following are the corresponding structures of the compounds ofExamples 1-14:

What is claimed is:
 1. A compound of formula I:

where R₁ is (C₁₋₆)alkyl or (C₃₋₆)cycloalkyl; R₂ is hydrogen or(C₁₋₆)alkyl; X is (C₁₋₁₂) alkylene; (C₂₋₁₂) alkenylene; or (C₂₋₁₂)alkynylene; m is 0 or 1; and R₃ is (C₃₋₈)cycloalkyl; or an aromatic ringsystem selected from II, III, IV and V:

where R₄ is hydrogen, chloro, or methoxy; R₅ is hydrogen, chloro,(C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH₃;or a pharmaceutically acceptable acid addition salt thereof, wherepossible.
 2. A compound of formula I according to claim 1 , where R₁ is(C₁₋₆) alkyl; R₂ is hydrogen or (C₁₋₄) alkyl; X is (C₁₋₆) alkylene or(C₂₋₆) alkenylene; m is 0 or 1; and R₃ is (C₃₋₈)cycloalkyl; or anaromatic ring system selected from II, III, IV and V where R₄ ishydrogen, chloro, or methoxy; R₅ is hydrogen, chloro, (C₁₋₁₈)alkyl or(C₁₋₁₈)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH₃; or apharmaceutically acceptable acid addition salt thereof, where possible.3. A compound of formula I according to claim 2 where R₁ is i-propyl ort-butyl; R₂ is hydrogen or methyl; m is 0 or 1; X is (C₁₋₆) alkylene;and R₃ is (C₅₋₇)cycloalkyl; or an aromatic ring system selected from IIaand V:

where R₄′ is in the meta position and is hydrogen or chloro; and R₅′ isin the para position and is hydrogen, chloro, (C₁₋₁₈)alkyl or(C₁₋₁₈)alkoxy; or a pharmaceutically acceptable acid addition saltthereof, where possible.
 4. A compound of formula I according to claim 3where R₁ is i-propyl or t-butyl; R₂ is hydrogen or methyl; m is 0 or 1;X is methylene or ethylene; and R₃ is (C₅₋₇)cycloalkyl, phenyl,3,4-dichlorophenyl, 4-methoxyphenyl, 4-n-decylphenyl, 4-n-decyloxyphenylor 3-pyridyl; with the proviso that when m is 0, R₃ is (C₅₋₇)cycloalkyl,4-n-decylphenyl or 4-n-decyloxyphenyl; or a pharmaceutically acceptableacid addition salt thereof, where possible.
 5. A compound of formula Iaccording to claim 1 , selected from3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide,and3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl]non-6-enamide,or a pharmaceutically acceptable acid addition salt thereof.
 6. Acompound of formula I according to claim 1 , selected from (2R, 3R, 4S,5R, 6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy2H-azepin-3-yl]non-6-enamide, and (2R, 3R, 4S, 5R,6E)-3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[(3S,6R)-hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy-2H-azepin-3-yl]non-6-enamide,or a pharmaceutically acceptable acid addition salt thereof.
 7. Apharmaceutical composition comprising a compound of formula I accordingto claim 1 , or a pharmaceutically acceptable acid addition saltthereof, where possible, together with a pharmaceutically acceptablecarrier.
 8. A pharmaceutical composition according to claim 7 comprisinga therapeutically effective amount of a compound of formula I which is3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.9. A pharmaceutical composition according to claim 7 comprising atherapeutically effective amount of a compound of formula I which is3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl]non-6-enamide.10. A method of treating tumors comprising administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundof formula I according to claim 1 , or a pharmaceutically acceptableacid addition salt thereof, where possible.
 11. A method of treatingtumors according to claim 10 comprising administering a therapeuticallyeffective amount of a compound of formula I which is3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(cyclohexylcarbonyl)oxy-2H-azepin-3-yl]non-6-enamide.12. A method of treating tumors according to claim 10 comprisingadministering a therapeutically effective amount of a compound offormula I which is3,4,5-trihydroxy-2-methoxy-8,8-dimethyl-N-[hexahydro-2-oxo-6-(1-oxo-3-phenylpropoxy)-2H-azepin-3-yl]non-6-enamide.13. A process for preparing a caprolactam compound of formula I

where R₁ is (C₁₋₆)alkyl or (C₃₋₆)cycloalkyl; R₂ is hydrogen or(C₁₋₆)alkyl; X is (C₁₋₁₂) alkylene; (C₂₋₁₂) alkenylene; or (C₂₋₁₂)alkynylene; m is 0 or 1; and R₃ is (C₃₋₈)cycloalkyl; or an aromatic ringsystem selected from II, III, IV and V:

where R₄ is hydrogen, chloro, or methoxy; R₅ is hydrogen, chloro,(C₁₋₁₈)alkyl or (C₁₋₁₈)alkoxy; and Z is oxygen, sulfur, N—H, or N—CH₃;or a pharmaceutically acceptable acid addition salt thereof, wherepossible, which process comprises, in a first step, acylating anaminocaprolactam compound of formula VI

with a lactone compound of formula VII

in the presence of a polar, organic solvent to obtain a diamide compoundof formula VIII

where each of R₁, R₂, X, m and R₃ is as defined in claim 1 and, in asecond step, hydrolyzing the diamide compound obtained in the first stepby dissolving it in a mixture of solvents to obtain the desiredcaprolactam compound of formula
 1. 14. A process according to claim 13wherein the acylation step is carried out in the presence of isopropanolat a temperature slightly below or at the reflux temperature of theisopropanol.